This Section carries out research on the mechanisms of growth regulation, focusing on the actions of insulin-like growth factors -I and -II (IGFs-I and -II). These growth factors have major roles in development as proven by the fact that targeted deletion of IGF-I and IGF-II gene expression results in severe dwarfism and, in the case of IGF-I, infertility in both sexes--although how IGF deletion causes these defects is not yet understood. The Section investigates the molecular mechanisms of IGF action in regulating growth and reproduction by utilizing these IGF "knockout" mice models. Over the past year the signal transduction pathways and biological functions of IGFs in the brain have been elucidated. Analysis of IGF-I null brains has revealed major disruptions of cerebral metabolism, including a decrease in neuronal hexokinase enzyme activity and protein expression and a decrease in glucose uptake which is restored by exogenous IGF-I. Pyruvate kinase, neuron-specific enolase, malate dehydrogenase and creatine kinase are also significantly altered in IGF-I null brains, demonstrating that absence of IGF-I results in major disruption of cerebral metabolic pathways and supporting the hypothesis that endogenous IGF-I acts as the brain's insulin. Other studies in the IGF-I null mice have shown that the S-phase of the cell-cycle appears to be prolonged in the knockouts, providing novel insight as to the mechanism of IGF-I's growth promoting effects. Studies on the role of the IGF system in reproduction have made substantial progress. Studies in the IGF-I knockout mouse have demonstrated that contrary to current views, IGF-I is not the mediator of estrogen's growth-promoting effects on the uterus, but rather is necessary for estrogen production. Other studies suggest that IGF-II deletion causes dwarfism primarily by attenuation of placental growth rather than by affecting the fetus directly.